Drug and Chemical Toxicology最新文献

Tripterygium wilfordii tablet (TWT) is a widely used therapeutic agent for rheumatoid arthritis, but its clinical utility is restricted by severe reproductive toxicity. This study aimed to elucidate the male reproductive toxic effects of TWT and its underlying mechanisms, focusing on the TGF-β1/Smad2/SF-1 signaling pathway, in which TGF-β1/Smad2 acts as the upstream regulatory module of SF-1. Fifty male Sprague-Dawley rats were randomized into five groups: normal control, collagen-induced arthritis (CIA) model, and low/middle/high-dose TWT-treated CIA groups. CIA was induced via bovine type II collagen immunization, and TWT was administered intragastrically for 21 or 42 days. In vitro, triptolide (TP), the core toxic component of TWT, was used to treat GC-2spd(ts) and TM3 cells. Key assays included Western blot and immunofluorescence for analyzing protein expression (TGF-β1, Smad2, SF-1) and localization; flow cytometry for cell cycle and apoptosis; transmission electron microscopy for ultrastructural changes; and histopathology for reproductive tissue damage. In vivo, TWT induced dose- and time-dependent reproductive dysfunction in CIA rats, characterized by reduced sperm count, increased sperm malformation, testicular/epididymal histopathological damage, decreased serum testosterone, and dysregulated expression of TGF-β1, Smad2, and SF-1. In vitro, TP inhibited cell viability, induced G1 phase arrest, apoptosis, and ultrastructural injury, with consistent perturbations in the TGF-β1/Smad2/SF-1 signaling pathway as observed in vivo. These findings demonstrate that TWT induces male reproductive toxicity in CIA rats and target cells through activating TGF-β1/Smad2 signaling and inhibiting SF-1, providing mechanistic insights into TWT-associated reproductive toxicity.

Triadimefon (TF) and triadimenol (TN) are triazole fungicides widely used to prevent fungal infections in cereals, fruits, and other economically important crops. Their harmful effects on non-target organisms have been reported. This study investigated the cytogenotoxic effects of TF and TN, isolated and combined, at environmentally relevant concentrations (TF: 0.006, 0.012, and 0.024 mg/mL; TN: 1.5, 3.0, and 6.0 mg/mL; and 0.012 mg/mL TF + 3.0 mg/mL TN) on human lymphocytes using the trypan blue exclusion test and the comet assay. Additionally, in silico tools, BioTransformer and DIGEP-Pred, were employed to elucidate metabolic pathways more effectively for detoxifying these xenobiotics and to evaluate their putative effects on gene transcription, respectively. Exposure to TF and TN, either alone or in combination, did not affect lymphocyte viability at the tested concentrations. However, both compounds induced an increase in the percentage of DNA strand breaks after treatment. The in silico predictions suggested that the interaction with the cytochrome P450 isoforms (CYP1A2, CYP2A6, CYP2C9, and CYP2D6) differed for each compound analyzed. Gene expression prediction indicated that TF and TN may up-regulate genes involved with hormonal alterations, Alzheimer's disease risk, and cancer progression (SF1, SPON1, ADGRF5, and RORB). While they may down-regulate a gene involved with changes in heart rhythm and neurotoxicity (HCN1). In conclusion, our findings reinforced that the triazole fungicides TF and TN, while effective in agriculture, may pose risks to genomic stability in humans, highlighting the importance of biomonitoring studies in exposed populations.

Drug-induced hepatotoxicity (DIH) is an adverse reaction secondary to the administration of anti-tuberculosis (anti-TB) drugs. We aimed to evaluate the importance of implementing periodic liver function tests before and throughout the anti-TB treatment course. Liver function tests were performed on recruited patients at baseline and periodically throughout the anti-TB treatment course (10 days, 3 months, and 6 months). Test results were collected for the predictive biomarkers: aspartate amino-transferase (AST), alanine amino-transferase (ALT), alkaline phosphatase (ALP), total bilirubin (TBil), and conjugated bilirubin (BC). Some patients were surveyed about their treatment course and any adverse drug reactions (ADRs) caused by anti-TB drugs. The mean values for each of the following markers spiked by 10 days of treatment: AST (73.235 ± 77.632 IU/L), ALT (77.537 ± 95.737 IU/L), TBil (9.460 ± 8.254 mg/L), and BC (1.476 ± 0.730 mg/L), then gradually stabilized by 3 and 6 months of treatment (except for BC levels, which showed slight fluctuations). The mean concentration levels of ALP were gradually increasing after 10 days and 3 months of treatment. Furthermore, the mean levels at baseline were significantly different from the mean levels in both 10 days and 3 months of treatment, for each of the following markers: AST (p < 0.01), ALT (p < 0.01), TBil (p < 0.05), and BC (p < 0.05). In this study, predictive biomarkers of liver function witnessed varying patterns of fluctuation throughout the anti-TB treatment course. The adherence of practitioners to a more standardized approach to TB treatment is vital for the early management of DIH.

Cadmium (Cd) is one of the most toxic heavy metals that are commonly present in the environment. Polyphenolic compounds exhibited the potential to mitigate heavy metal-induced organ toxicity. Crocin is a carotenoid compound of saffron. This study investigated the protective potential of crocin against cadmium chloride (CdCl₂)-induced oxidative pancreatitis and liver injury in female rats. Rats were placed into four groups: negative control (NC), CdCl₂- rats (successive 1 and 3 mg/kg bodyweight, per week for 2 weeks), crocin negative control (Crocin NC), and co-treated CdCl₂ rats and crocin (50 mg/kg bodyweight for 14 days, oral). Pancreatic contents of malondialdehyde (MDA) and glutathione (GSH) were measured. Serum levels of total antioxidant capacity (TAC), glucose, alpha-amylase, neuropeptide Y (NPY), and hydroxyproline (HPY) were estimated. Histopathological analyses of the pancreas and liver were conducted. CdCl₂ elicited oxidative stress, increased glucose levels, activated α-amylase, and elevated NPY and HPY levels. These biochemical findings ran in harmony with histological findings. Co-treatment of CdCl₂-rats with crocin mitigated oxidative stress, inflammation, metabolic dysregulation, and liver fibrosis. This study suggests that crocin may exhibit protective potential against Cd-induced pancreatitis and hepatotoxicity and may highlight the potential use of NPY and HPY as diagnostic biomarkers in heavy metals-associated toxicities.

Trifloxystrobin (TFX) is a strobilurin fungicide that has a lipophilic nature, which allows it to accumulate in the brain. Therefore, it is crucial to investigate effective methods for preventing brain damage caused by TFX. We aimed to assess the protective benefits of myricetin (MYR) against toxicities brought on by TFX. SH-SY5Y cells were exposed to an inhibiting concentration of 50% (IC50) of TFX (100 µM), and the protective effect of MYR was tested at concentrations of 5, 10, 20, and 50 µM. Cell viability, oxidative stress, and integrated stress response (ISR) activation via the DELE1-HRI pathway were used to assess cytotoxicity. Apoptosis was evaluated by measuring phosphatidylserine externalization, cytochrome c release, Bax and caspase 3 activation, and loss of mitochondrial transmembrane potential (ΔΨm). Results showed that TFX (100 µM) significantly decreased cell viability and increased reactive oxygen species (ROS) generation, malondialdehyde (MDA) production, and superoxide dismutase (SOD)/catalase (CAT) activities. However, pretreatment with 50 µM MYR significantly restored cell viability to nearly 100% compared to control cells. Furthermore, MYR pretreatment inhibited ISR activation by reducing ATF4 and CHOP expression and decreased apoptosis in a dose-dependent manner. These quantitative results point to MYR as a potent natural substance that may protect cells from TFX-induced neurotoxicity.

Selenium exposure via air can occur in the environment and workplace. To protect humans it is important to determine the concentrations at which different forms of selenium are toxic. We reviewed the literature on 1) selenium environmental and occupational air concentrations and 2) biokinetics and toxicity after pulmonary exposure. Environmental selenium ranged between 0.1 to 20 ng/m³, while occupational selenium was up to 2 mg/m³. Inhaled selenium distributes to blood and as demonstrated in animals to the internal organs. Excretion has been demonstrated to occur via urine, feces and breath. Toxicity data are scarce: two studies with occupational exposure to elemental selenium showed no effect at 0.11 and 0.32 mg Se/m³. In guinea pigs, inhalation of elemental selenium indicated a lowest-observed-adverse-effect concentration (LOAEC) of 33 mg Se/m³ on affected lung and spleen (no controls available). Inhalation of hydrogen selenide in the same species resulted in a LOAEC of 1 mg Se/m³ on lethality. Animal studies using intratracheal instillation resulted in lowest-observed-adverse-effect levels (LOAELs) set on lung function of 0.06 mg Se/kg bodyweight (bw) (selenite), and 0.6 mg Se/kg bw (selenium dioxide). For dimethyl selenide, a LOAEL on lethality was 0.1 mg Se/kg bw. In conclusion, environmental selenium ranges from 0.1 to 20 ng Se/m³, while occupational selenium levels can be magnitudes higher. Selenium distributes to blood and internal organs after pulmonary exposure. Animal inhalation studies indicate LOAECs of 1 and 33 mg Se/m³, while LOAELs of intratracheal instillation studies start at 0.06 mg Se/kg bw.

This study assessed the cardiotoxic effect of post-weaning BPA exposure and the potential ameliorative effect of silymarin on BPA-induced cardiotoxicity. Twenty-four male Wistar rats were randomized into four groups: the control, silymarin-treated, bisphenol A (BPA)-treated, and the BPA+silymarin-treated. Post-weaning BPA exposure led to a rise in cardiac injury markers, malondialdehyde, and iron contents, and a reduction in GSH and GPX4. Moreover, BPA elevated cardiac TNF-α, IL-1β, MPO, VCAM-1, NF-kB, TLR4, caspase 3, cytochrome c, and DFI. Additionally, BPA promoted amyloid accumulation and distorted cardiac histoarchitecture. Nonetheless, silymarin treatment attenuated BPA-induced biochemical and histological alterations. In conclusion, silymarin attenuated BPA-induced cardiotoxicity, potentially via modulation of TLR4/VCAM signaling. Further studies are needed to confirm these mechanisms.

Centratherum punctatum (Asteraceae), known as Brazilian bachelor's button, is used in folk medicine to treat liver problems, intestinal discomfort, and ulcers. The study aims to characterize the ethanolic extract (EE) of C. punctatum leaves, evaluate its antioxidant activity, and assess its cytogenotoxic and chemoprotective effects in Allium cepa and Drosophila melanogaster cells. The EE was characterized by qualitative phytochemical prospecting, TLC, ESI-IT/MSⁿ, HPLC-PDA, and isolation by column chromatography. Antioxidant activity (DPPH and ABTS) and total phenol content (TPC) were quantified. Cytogenotoxicity and the protective effect of EE were evaluated in the A. cepa and the somatic mutation and recombination test (SMART) bioassays at concentrations of 3.9; 15.6; 62.5 and 250 µg/mL. The phytochemical prospecting of EE revealed the presence of tannins, saponins, flavanones, alkaloids, terpenes, and flavonoids. ESI-IT/MSⁿ identified 15 compounds, HPLC-PDA also confirmed the same classes of metabolites, and the isolate was the triterpene acetyl aleuritolic acid. The result of DPPH, ABTS, and TPC was 142.10 ± 2.15 µg/mL; 623.94 ± 38.38 mM Trolox/g, and 77.78 ± 1.19 mg EAG/g, respectively. In A. cepa and SMART, none of the EE concentrations were cytogenotoxic. EE showed a protective effect (pre, simultaneous, and post-treatments) against methyl methanesulfonate damage at all concentrations in A. cepa and antigenotoxic activity (simultaneous) in SMART at 15.6; 62.5, and 250 µg/mL against doxorubicin damage. The findings of the present study demonstrate that C. punctatum is a promising source of compounds with antioxidant and chemoprotective properties.

Background: Premature ovarian insufficiency (POI) is a complex disorder with diverse etiologies that profoundly impacts female fertility and overall health. Acetyl tributyl citrate (ATBC), a commonly used plasticizer in consumer products, has recently drawn attention for its potential role in disrupting ovarian function.

Methods: ATBC-associated targets were predicted using STITCH and Swiss Target Prediction tools. Genes implicated in POI were retrieved from the GeneCards and OMIM databases. Overlapping targets were identified and used to construct a protein-protein interaction (PPI) network through the STRING platform, with core targets visualized and analyzed using Cytoscape. Functional enrichment analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, were conducted to determine relevant biological processes and signaling pathways. Molecular docking was performed to evaluate the binding interactions between ATBC and the core target proteins.

Results: A total of 84 overlapping targets were identified as potential mediators of ATBC-induced POI. PPI analysis highlighted five central hub proteins: STAT3, EGFR, PIK3CA, MMP9, and PRKCA. Enrichment analyses suggested involvement in oxidative stress, lysosomal activity, and serine/threonine kinase signaling. Key pathways included PI3K-AKT, MAPK, apoptosis, GnRH, and HIF-1 signaling cascades. Molecular docking results demonstrated favorable binding affinities between ATBC and the hub proteins.

Conclusion: This integrative study sheds light on the molecular mechanisms by which ATBC may contribute to POI. By identifying critical targets and pathways, our findings provide a foundation for further toxicological research and underscore the utility of combining computational prediction, network analysis to assess the reproductive risks of environmental contaminants.

1,3-Dichloro-2-propanol (1,3-DCP) is a moderately volatile organic compound with industrial applications in food and water processing, but it exhibits high reactivity with lipid-rich tissues. This study examines the effect of 1,3-DCP on reproductive fertility parameters in male Wistar rats. Male animals weighing 250 ± 50 grams were assigned randomly to five groups (A-E). Group A received distilled water (control), while groups B-E received oral doses of 5, 10, 15, and 20 mg/kg BW 1,3-DCP for 28 days. Then, analysis was conducted to evaluate the experimental animals' hormonal profiles, spermatogenic activity, testicular function markers, and enzymatic antioxidant status. Oral administration of the chemical caused a significant decrease in body weight, testicular weight, and testes/body weight ratio as well as cholesterol levels in serum and testicular homogenate. While the compound decreased testosterone, luteinizing and follicle-stimulating hormone concentrations, it also lowered alkaline phosphatase, acid phosphatase, and gamma-glutamyl transferase concentrations in testicular tissue samples. Increased malondialdehyde levels, accompanied by a corresponding reduction in glutathione, catalase, and superoxide dismutase in the testicular homogenate, suggest that 1,3-DCP administration resulted in reactive oxygen species-mediated oxidative stress, leading to a consequent decrease in sperm count and abnormalities in spermatozoa morphology. The findings of this study revealed that 1,3-DCP has antifertility effects in male Wistar rats.